The invention disclosed herein relates to radioactive implants for medical therapeutic purposes, referred to in the art as xe2x80x9cradioactive seeds,xe2x80x9d xe2x80x9cseeds,xe2x80x9d or xe2x80x9csources.xe2x80x9d The invention relates to seeds for therapeutic radiation treatment of oncological and other medical conditions. More particularly, the invention is directed to a novel radioactive seed for interstitial implantation brachytherapy and also for general brachytherapy treatments. The invention is also directed to methods of making the seeds and methods of using the seeds.
The localized treatment of tumors and other medical conditions by the interstitial implantation of radioactive materials is a recognized treatment modality of long standing. Radioactive implants are used to provide radiation therapy in order to reduce or prevent the growth of tumors that cannot be removed by surgical means. Radioactive implants are also used to prevent the growth of microscopic metastatic deposits in lymph nodes that drain the region where a tumor has been removed. Implants are also used to irradiate the postoperative tumor bed after the tumor is excised. Implantation of radioactive sources directly into solid tumors for the destruction of the tumors is used in a therapy referred to as brachytherapy.
Brachytherapy is also used to prevent the regrowth of tissue in circumstances such as the treatment of arteries for occlusive disease. Brachytherapy is applied, for example, in the treatment of atherosclerosis to inhibit restenosis of blood vessels after balloon-angioplasty or other treatments to open occluded or narrowed vessels. These brachytherapy treatments involve a short-term application of extremely radioactive sources. The applications can be for periods as short as a few minutes. This form of brachytherapy may therefore be contrasted with the treatment of tumors where lower activity sources are used for longer periods of time that may be measured in hours or days or may involve permanent implantation.
Treatment of medical conditions with the local application of radiation by implantation concentrates the treatment on the adjacent tissue and advantageously minimizes the exposure of more distant tissues that it is not desired to irradiate. Direct implantation of radioactive sources into tumors often permits the application of larger doses of radiation than may otherwise be achieved because the radiation is applied directly at the site to be irradiated. Local application of brachytherapy to non-cancerous conditions also allows the use of more intensive treatment than is possible by other means.
In the prior art, brachytherapy xe2x80x9csourcesxe2x80x9d are generally implanted for short periods of time and usually are sources of high radiation intensity. For example, irradiation of body cavities such as the uterus has been achieved by placing radium-226 capsules or cesium-137 capsules in the lumen of the organ. In another example, tumors have been treated by the surgical insertion of radium needles or iridium-192 ribbons into the body of the tumor. In yet other instances gold-198 or radon-222 have been used as radioactive sources. These isotopes require careful handling because they emit highly energetic and penetrating radiation that can cause significant exposure to medical personnel and to the normal tissues of the patient undergoing therapy. Therapy with sources of this type requires that hospitals build shielded rooms, provide medical personnel with appropriate protection and establish protocols to manage the radiation hazards.
The prior art interstitial brachytherapy treatment using needles or ribbons has features that inevitably irradiate normal tissues. For example, normal tissue surrounding the tumor is irradiated when a high energy isotope is used even though the radiation dose falls as the square of the distance from the source. Brachytherapy with devices that utilize radium-226, cesium-137 or iridium-192 is hazardous to both the patient and the medical personnel involved because of the high energy of the radioactive emissions. The implanted radioactive objects can only be left in place temporarily; thus the patient must undergo both an implantation and removal procedure. Medical personnel are thus twice exposed to a radiation hazard.
In prior art brachytherapy that uses long-term or permanent implantation, the radioactive device is usually referred to as a xe2x80x9cseed.xe2x80x9d Where the radiation seed is implanted directly into the diseased tissue, this form of therapy is referred to as interstitial brachytherapy. It may be distinguished from intracavitary therapy, where the radiation seed or source is arranged in a suitable applicator to irradiate the walls of a body cavity from the lumen.
Migration of the device away from the site of implantation is a problem sometimes encountered with presently available iodine-125 and palladium-103 permanently implanted brachytherapy devices because no means of affirmatively localizing the device may be available.
The prior art discloses iodine seeds that can be temporarily or permanently implanted. The iodine seeds disclosed in the prior art consist of the radionuclide adsorbed onto a carrier that is enclosed within a welded metal tube. Seeds of this type are relatively small and usually a large number of them are implanted in the human body to achieve a therapeutic effect. Individual seeds of this kind described in the prior art also intrinsically produce an inhomogeneous radiation field due to the form of the construction.
The prior art also discloses sources constructed by enclosing iridium metal in plastic tubing. These sources are then temporarily implanted into accessible tissues for time periods of hours or days. These sources must be removed and, as a consequence, their application is limited to readily accessible body sites.
Prior art seeds typically are formed in a manner that differs from isotope to isotope. The form of the prior art seeds is thus tailored to the particular characteristics of the isotope to be used. Therefore, a particular type of prior art seed provides radiation only in the narrow range of energies available from the particular isotope used.
Brachytherapy seed sources are disclosed in, for example, U.S. Pat. No. 5,405,165 to Carden, U.S. Pat. No. 5,354,257 to Roubin, U.S. Pat. No. 5,342,283 to Good, U.S. Pat. No. 4,891,165 to Suthanthiran, U.S. Pat. No. 4,702,228 to Russell et al, U.S. Pat. No. 4,323,055 to Kubiatowicz and U.S. Pat. No. 3,351,049 to Lawrence, the disclosures of which are incorporated herein by reference.
The brachytherapy seed source disclosed in U.S. Pat. No. 5,405,165 comprises small cylinders or pellets on which palladium-103 compounded with non-radioactive palladium has been applied by electroplating. Addition of palladium to palladium-103 permits electroplating to be achieved and allows adjustment of the total activity of the resulting seed. The pellets are placed inside a titanium tube, both ends of which are sealed. The disclosed invention does not provide means to fix the seed source within the tissues of the patient to ensure that the radiation is correctly delivered. The design of the seed source is such that the source produces an asymmetrical radiation field due to the radioactive material being located only on the pellets. The patent also discloses the use of end caps to seal the tube and the presence of a radiographically detectable marker inside the tube between the pellets.
U.S. Pat. No. 5,354,257 relates to radioactive iridium metal brachytherapy devices positioned at the end of minimally invasive intravascular medical devices for providing radiation treatment in a body cavity. Flexible elongated members are disclosed that can be inserted through catheters to reach sites where radiation treatment is desired to be applied that can be reached via vessels of the body.
U.S. Pat. No. 5,342,238 discloses methods such as sputtering for applying radioactive metals to solid manufactured elements such as microspheres, wires and ribbons. The disclosed methods are also disclosed to apply protective layers and identification layers. Also disclosed are the resulting solid, multilayered, seamless elements that can be implanted individually or combined in intracavitary application devices.
U.S. Pat. No. 4,891,165 to Suthanthiran relates to the production of brachytherapy seed sources and discloses a technique for use in the production of such sources. The patent discloses an encapsulation technique employing two or more interfitting sleeves with closed bottom portions. The open end portion of one sleeve is designed to accept the open end portion of a second slightly-smaller-diameter sleeve. The patent discloses the formation of a sealed source by sliding two sleeves together. Seeds formed by the Suthanthiran process may have a more uniform radiation field than the seed disclosed by U.S. Pat. No. 5,405,165. However, the seed disclosed by Suthanthiran provides no means for securely locating the seed in the tissue of the patient. The U.S. Pat. No. 4,702,228 to Russell et al. relates to the production of brachytherapy seed sources produced by the transmutation of isotopically enriched palladium-102 to palladium-103 by neutrons produced by a nuclear reactor. The Russell patent also discloses a titanium seed with sealed ends, similar to that of Carden, containing a multiplicity of components. A seed produced in this manner is associated with yielding a less than isotropic radiation field.
U.S. Pat. No. 4,323,055 teaches a titanium seed with ends sealed by laser, electron beam or tungsten inert gas welding. The radioactive component of the seed is disclosed to be a silver bar onto which the radioisotope iodine-125 is chemisorbed. Seeds produced in this manner also tend to produce an asymmetric radiation field and provide no means of attachment to the site of application in the patient.
U.S. Pat. No. 3,351,049 discloses a radioactive seed with a titanium or plastic shell with sealed ends. Seeds are disclosed containing a variety of cylindrical or pellet components onto which one of the radioisotopes iodine-125, palladium-103, iridium-192 or cesium-131 is incorporated. The structure of the disclosed seeds yields a non-homogeneous radiation field and provides no means for accurately positioning the seed in the tissue that it is desired to irradiate.
Currently available brachytherapy seeds do not easily lend themselves to association with suture material. For example, iodine-125 seeds currently in use are placed inside suture material at the time of manufacture. However, the insertion process is tedious and time consuming and has the potential for significant radiation exposure to the production personnel involved. Additionally, because of the natural decay of the radioisotope, the suture material thus produced has a short shelf life. As a second example, the manufacturing process used to produce the palladium-103 seeds that are currently in use results in end-roughness of the encapsulation of the seed. The capsules are not placed inside suture material because the end-roughness makes insertion very difficult. Rigid rods are produced in present technology by the insertion of seeds into suture material followed by heat treatment to form a rigid rod containing the seed. These rods are difficult to produce, very fragile and sensitive to moisture. The presently available brachytherapy technology requires that most physicians use suture material preassembled with the seeds already inside. Similarly, rigid materials used by surgeons for brachytherapy are pre-manufactured and purchased readymade.
The present invention provides a novel general-use brachytherapy device for the interstitial radiotherapy of malignant neoplasms or other diseases treatable with radiation. The device of the instant invention comprises a hollow tubular support with a lumen that is open on both ends. The tubular support of the device bears a radioactive layer that is enclosed with a sealing layer to prevent contact between the radioactive material and the tissues and fluids of the patient.
The hollow tubular support of the present invention comprises a hollow-tube-shaped seed-substrate that has internal and external surfaces. Other embodiments of the instant invention have perforations through the walls of the hollow tube. In embodiments that have perforations through the walls of the tube, the perforations may be oriented in any direction. The various elements of the device may be made of titanium or other biocompatible metal or may be made of synthetic material such as plastic.
The radioactive source material is disposed as a layer on the external surface of the tube of the device. Other materials, such as radiographically detectable material, may also be layered on the external surface of the tube of the device. The entire device is provided with a biologically-compatible, radiation-permeable, surface-sealing layer that entirely seals the external surface of the tube.
An object of the invention disclosed herein is to provide for the improved treatment of medical conditions such as neoplastic diseases according to the normal practice of brachytherapy, e.g., the interstitial implantation of radioactive sources into tumorous tissue for the purpose of irradiating and thus killing malignant cells.
An object of the invention disclosed herein is to provide a brachytherapy device specifically intended to ease the task of surgeons, urologists, radiation therapists, radiologists and others who use brachytherapy devices in providing treatment to patients. The hollow tubular design promotes simple and efficient interaction between the device and suture materials commonly used in surgery. Simply stated, the hollow-tube-shaped form of the device disclosed herein permits suture material, rigid rods or other biocompatible connecting members to be passed through it in such a way as to fix its position relative to the treatment volume. The suture material, rigid rod or other biocompatible connecting member may be threaded through the device at the time of surgery and can also serve to locate the device relative to other similar devices. This flexibility allows a surgeon to effectively react to challenges not revealed by the pre-surgical work-up of the patient.
The design of the invention disclosed herein promotes simple and efficient interaction between the device and suture materials commonly used in surgery. Thus, the brachytherapy device disclosed herein has special application to the form of brachytherapy wherein seeds are associated with flexible suture material and are thereby held in a compliant array in the neoplastic tissue by the suture while their radiation dose is delivered. This greatly speeds and simplifies the process of applying the brachytherapy device, greatly improves the accuracy of emplacement in the tumor and reduces the hazard to which medical personnel are exposed.
The hollow-tube feature of the invention disclosed herein also has special application to the form of brachytherapy in which seeds are associated with a rigid, biocompatible material which holds the seeds in a fixed array in the neoplastic tissue while their radiation dose is delivered. In a similar manner to that described above the disclosed device may be simply threaded onto any commonly used rigid support material to yield a suitable array. For example a hollow-tube brachytherapy device as disclosed herein may be applied by threading a surgical stainless-steel wire or plastic surgical filament through the lumen. The threaded material may then be used to fix the device to the catheter. The catheter is then used to position the array at a site where brachytherapy is needed.
The most preferred overall dimensions of the device disclosed herein may be a diameter of approximately 0.8 mm and a length of approximately 4.5 mm. The advantage of providing a seed in these dimensions is that the device of the present invention may be implanted using currently available instruments. Thus, the need for retooling by the therapist may be avoided, and a brachytherapy device that incorporates the seed-substrate of the instant invention may be applied without modification of current surgical practices. Alternatively, the dimensions of the seed-substrate may be different from those disclosed above, depending upon the specific use to which the device is to be put. Such different dimensions will be apparent to those of skill in the art.
The devices disclosed herein are designed to deliver a therapeutic dose of radiation to a spatially well defined and limited volume of diseased tissue within a living body. Such a device is shaped as a hollow tube so that a suture material, rigid rod or other biocompatible connecting member passed through it can be used to fix its position relative to other similar devices. The threaded connecting member can also serve to locate the device relative to the treatment volume.
The hollow-tube design of the device of the present invention also permits the growth of tissue into the device. This tissue growth acts to anchor the device at the application site and minimize the potential for migration. In embodiments of the device provided with perforations, the perforations also provide additional access for body fluids and tissues to the space inside the tube.
Another object of the invention disclosed herein is to provide an embodiment of the device that has its central tube-shaped substrate formed from a material that is essentially transparent to the radiation emitted by the therapeutic isotope. Such material may be titanium, carbon, stainless-steel, tantalum, hafnium or zirconium. The central tube may also be formed from plastics such as polypropylene, polyethylene terephthalate, nylon, polyurethane, polyphenylene oxide blends, polyphenylsulfone, polysulfone, polyether sulfone, polyphenylene sulfide, phenyletheretherketone, polyetherimide or liquid crystal polymer.
The radioactive material of the embodiments of the invention as disclosed herein is coated on the outer surface of the hollow-tube-shaped seed-substrate and is protected by the sealing layer. Suitable radioisotopes are palladium-103 or iodine-125. Other isotopes that emit radiation with the desired therapeutic properties can also be deposited over the outer surface of the tube in a uniform manner, for example gold-198, yttrium-90 and phosphorus-32. The radioactive material in this layer may already be radioactive when it is applied such as by the application of palladium-103 or iodine-125, or it may be applied as a precursor isotope such as gold-197, yttrium-89, iridium-191 or palladium-102 that can be applied and then transmuted in situ, as disclosed in more detail below.
In yet another embodiment of the instant invention a non-radioactive pre-seed is disclosed. In this embodiment the layer of the device that will be radiation-emitting may be prepared by first plating the hollow-tube-shaped seed-substrate with a suitable non-radioactive isotope that may be transmuted in situ to the desired radiation-emitting isotope by bombardment with neutrons. The material in this layer may be a precursor isotope such as gold-197, yttrium-89, iridium-191 or palladium-102. Upon neutron irradiation gold-197 is transmuted to xe2x80x9cgold-198xe2x80x9d (which is actually a mixture of gold-198 and gold-199) with a half-life of 2.7 days and with radiation-emitting properties suitable for brachytherapy. For simplicity this isotope produced by this transmutation is referred to hereinafter as xe2x80x9cgold-198.xe2x80x9d Similar processes or transmutation can be used to produce yttrium-90 from yttrium-98 or palladium-103 from palladium-102.
A particular advantage of this technique is that the time and intensity of the neutron irradiation can be adjusted to achieve a particular desired level of activity in the finished device. The technique of neutron irradiation takes advantage of the fact that titanium and some other low-atomic-number metals have small nuclear cross-sections and are essentially unaffected by neutron irradiation. A further advantage of this embodiment of the invention is that no radioactive material is used in the actual manufacturing of the device. A third advantage is that manufactured devices may be stored indefinitely and may be rendered radioactive when needed by exposure to neutron irradiation from a nuclear reactor or cyclotron or other suitable source.
In such an embodiment of the invention, the transmutable non-radioactive isotope is first plated onto the hollow-tube-shaped seed-substrate. Second, the plated hollow-tube seed-substrate is inserted into a closely fitting outer tube of the same length, or slightly longer if the outer tube is to be swaged, that provides the sealing layer. This outer tube can be a metal such as titanium, and is made so that this sealing member or outer tube, fits snugly over the inner tube coated with the radioisotope and radiographically detectable band (if present). The ends of the inner and outer tubes are swaged together and joined, for example by laser welding, so as to form a sealed device. The sealed device thus formed has the form of a double-walled tube. The sealing layer may also be formed from stainless-steel, tantalum, hafnium or zirconium.
Alternatively, the outer tube can also be a synthetic material, such as one of the plastics mentioned above, made so that this sealing member or outer tube fits snugly over the inner tube coated with the radioisotope and radiographically-detectable band (if present). In the case of a plastic sealing member the ends of the inner and outer tubes can be sealed by standard techniques like gluing, heat sealing, solvent bonding or ultrasonic welding.
In yet another embodiment of the sealing layer, a material that is essentially transparent to the radiations emitted by the therapeutic isotope is deposited upon the surface. For example, the sealing layer may be made of a material such as pyrolytic carbon deposited from a chemical vapor or such as titanium deposited from an atomic vapor. The sealing layer may also be formed from carbon, tantalum, hafnium or zirconium, or may be formed from titanium carbide, titanium nitride, titanium carbonitride, hafnium nitride, or zirconium nitride.
Alternatively, in another embodiment of the invention disclosed herein the sealing layer may consist essentially of an organic coating, as for example an organic coating formed from a heat-shrinkable plastic, a coating produced by solvent evaporation, a coating produced by a chemical polymerization reaction or a coating formed by molding plastic around the device. Such organic coatings may be polypropylene, polyethylene terephthalate, nylon, polyurethane, polyphenylene oxide blends, polyphenylsulfone, polysulfone, polyether sulfone, polyphenylene sulfide, phenyletheretherketone, polyetherimide or liquid crystal polymer.
Another feature of the invention disclosed herein provides advantages in situations in which a remote afterloading technique is used. For example, remote afterloading may be used with implants that are temporary implants in the brain. The form of the brachytherapy device disclosed herein offers advantages because isotopes incorporated into these sources (palladium-103 or iodine-125) emit X-rays of average energy between 21 and 30 keV. A consequence of this low energy is to greatly simplify shielding. For example, the half-value thickness (the thickness of lead required to reduce the dose rate from a source to 50%) is only 0.006 mm for palladium-103 and 0.02 mm for iodine-125.
Because the devices disclosed herein are simple to shield, most of the features normally associated with brachytherapy techniques that involve remote afterloading are not applicable. Use of the devices disclosed herein would generally not require remote transfer of the radiation source from a shielded container into the tube implanted in the patient. Similarly, the necessity to isolate the patient in a shielded room during treatment is generally avoided with the disclosed devices. Isotopes incorporated into other embodiments of the device emit beta-particles rather than electromagnetic radiations. These beta-particle emitting embodiments are advantageous in that they may also be effectively shielded by much smaller combinations of plastic and lead than those required by previously available afterloader sources.
Localization of sources following implantation is of importance because accurate knowledge of the position and orientation of the sources can confirm that they are in the positions specified in the medical treatment plan and consequently will provide a properly distributed radiation dose within the treatment volume. To provide means whereby the device can be located after implantation, one embodiment of the present invention is formed with radiographically opaque material such as gold, platinum or other appropriate high-atomic-number element deposited on the device, preferably as a band on the surface near the center of the device. This radiopaque material allows the visualization of the implanted device by standard radiographic procedures and allows the location and orientation to be accurately determined during treatment.
When the radioactive material is applied to an embodiment of the invention that bears a band of radiographically detectable material, the radioactive material may extend over the band of radiographically detectable material. In another embodiment the radioactive material may extend only to within approximately 0.5 mm of the end edge of the tube-shaped seed-substrate and thus provide a narrow nonradioactive ring at each end of the device. Generally, the radioactive material may be disposed on the device to suit many purposes that will be obvious to those of skill in the art.
In preferred embodiments of the present invention, a biocompatible sealing layer is deposited so that the entire external surfaces of the device are composed of a biocompatible material. The sealing layer prevents radioactive materials from escaping and provides a radioactive device which meets the normal definition of a xe2x80x9csealed source.xe2x80x9d The sealing layer is made of a plastic material or any other biocompatible material, provided the material is adequately transparent to the therapeutic radiation and has sufficient durability to protect and retain the radioisotope underneath. In another embodiment the sealing layer can be made of titanium or other suitable biocompatible metal that is adequately transparent to the therapeutic radiation.
The device disclosed herein will be used for the treatment of medical conditions such as neoplastic diseases according to the normal practice of brachytherapy, e.g., the interstitial implantation of radioactive sources into tumorous tissue for the purpose of irradiating and thus killing malignant cells. Other uses are the emplacement into vessels of the body, e.g., to inhibit restenosis of blood vessels.